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Cell-cell communication among all cell types in the periodontal osteoimmunology microenvironment. A. The circo plot showing the potential cell interactions among ten major cell types as in Figure 1B in periodontal tissues predicted by CellphoneDB. The node size represents the number of interactions. The width of the edge represents the number of significant ligand-receptor pairs between the two cell types. B. Venn diagram representing the interaction between the significant ligand-receptor pairs identified by CellPhone-DB analysis on scRNA-seq data from HC, PD, and PDT samples. C. The dot plot generated by CellPhoneDB showing potential ligand-receptor pairs associated with osteoblastogenesis between Pre-OB and all detected cellular types in PD group. Dots colored by mean expression of ligand-receptor pair between two clusters
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Single-cell RNA sequencing (scRNA-seq) enables specific profiling of cell populations at single-cell resolution. The osteoimmunology microenvironment in the occurrence and development of periodontitis remains poorly understood at the single-cell level. In this study, we used single-cell transcriptomics to comprehensively reveal the complexities of...
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... we used CellPhoneDB (Method) to identify ligand-receptor pairs among the major cell types shown in Figure 1 to explore possible molecular interactions. The circos plot detected broadcast ligands and demonstrated extensive communication for cognate receptors ( Figure 7A and Figure S10). Notably, endothelial cells showed the most interactions with other cell types, followed by fibroblasts, monocytic cells, and epithelial cells. ...
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... there were 26942 pairs in common among the three groups. There were 13018, 13047, and 13784 unique ligand-receptor interaction pairs in the HC, PD, and PDT groups, respectively ( Figure 7B). Since pre-OBs and OCPs give rise to osteoblasts and osteoclasts, respectively, we further calculated the attraction strengths of ligand-receptor pairs in our scRNA-seq dataset and identified interaction pairs displaying significant cell population specificity between pre-OBs/OCPs and other cells. ...
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... most specific interactions between pre-OBs and other cell types were observed with osteoblastogenesis (such as Wnt, BMP, PDGF, FGF, and NOTCH signaling), and were more abundant in the PD group than the HC group or PDT group ( Figure 7C and Figure S11). Notably, pre-OBs in the PD group expressed relatively high levels of the NOTCH receptors, while the corresponding ligands were widely expressed in endothelial cells, suggesting a strong interaction between pre-OBs and ECs during the osteoblastogenic process [71]. ...
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... analyses showed apparently increased interactions of receptor-ligand pairs associated with Ephrin-Eph signaling between ECs and Pre-OB, such as EFNA1-EPHA7, EPHA2-EFNA5, EPHA4-EFNB3, EPHA4-EFNA5, and EPHB4-EFNB3 ( Figure 7D-E, Figure S12, and Table S9). We next examined the anatomic relationship between Ephrin A1-expressing ECs (CD31 + ) and Eph A7-expressing Pre-OBs (ALP + ) in periodontal tissues from HC and PD samples, using quadruple immunofluorescence (IF) staining on paraffin section. ...
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... observed numerous Eph A7 + ALP + Pre-OBs on alveolar bone surfaces in samples from HC group. In contrast, Eph A7 + ALP + Pre-OBs numbers in PD samples were markedly reduced, and numerous Ephrin A1-expressing ECs were detected ( Figure 7F). ...
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... potential cross-talks with the focus on the osteoimmunology microenvironment of periodontal tissue after initial periodontal therapy could be abstracted from our data (Figure 7, Figure S10-13, and Table S9) as exemplified in Figure 8. These scRNA-seq data were direct evidence for a shared regulatory network among osteoimmune cells in periodontal tissue after initial periodontal therapy. ...
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... membranebound molecules mediate contact-dependent and bidirectional signaling through both the Eph receptors (termed forward signaling) and ephrin ligands (referred to as reverse signaling) [88]. In our study, the pronounced changes in the expression of Ephrin-Eph interactions indicated that they may play distinct roles in modulating the process of periodontitis (Figure 7, Figure S13, and Table S9). Evidence suggests that ephrin ligands and Eph receptors are crucial signaling molecules, contributing to fibroblast activation, extracellular matrix deposition, and tissue fibrosis formation [89][90][91][92]. ...
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... current study reveals the function of venous ECs in the recruitment of T cells via the production of proinflammatory cytokines and chemokines ( Figure 5 and Figure S6). New research has revealed that ECs have many innate immune functions, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular pattern-and danger-associated molecular pattern sensing, proinflammatory, immuneenhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity, suggesting ECs are novel immune cells [107][108][109][110]. Along these lines, our data suggest ECs produce multiple proinflammatory cytokines/chemokines and possess the most interactions with other cell types ( Figure 5, Figure 7, and Table S9). In addition, the interactions related to OB differentiation were most enriched between ECs and pre-OBs ( Figure 7 and Table S9). ...
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... research has revealed that ECs have many innate immune functions, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular pattern-and danger-associated molecular pattern sensing, proinflammatory, immuneenhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity, suggesting ECs are novel immune cells [107][108][109][110]. Along these lines, our data suggest ECs produce multiple proinflammatory cytokines/chemokines and possess the most interactions with other cell types ( Figure 5, Figure 7, and Table S9). In addition, the interactions related to OB differentiation were most enriched between ECs and pre-OBs ( Figure 7 and Table S9). Thus, we agree with the concept that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. ...
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... we used CellPhoneDB (Method) to identify ligand-receptor pairs among the major cell types shown in Figure 1 to explore possible molecular interactions. The circos plot detected broadcast ligands and demonstrated extensive communication for cognate receptors ( Figure 7A and Figure S10). Notably, endothelial cells showed the most interactions with other cell types, followed by fibroblasts, monocytic cells, and epithelial cells. ...
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... there were 26942 pairs in common among the three groups. There were 13018, 13047, and 13784 unique ligand-receptor interaction pairs in the HC, PD, and PDT groups, respectively ( Figure 7B). Since pre-OBs and OCPs give rise to osteoblasts and osteoclasts, respectively, we further calculated the attraction strengths of ligand-receptor pairs in our scRNA-seq dataset and identified interaction pairs displaying significant cell population specificity between pre-OBs/OCPs and other cells. ...
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... most specific interactions between pre-OBs and other cell types were observed with osteoblastogenesis (such as Wnt, BMP, PDGF, FGF, and NOTCH signaling), and were more abundant in the PD group than the HC group or PDT group ( Figure 7C and Figure S11). Notably, pre-OBs in the PD group expressed relatively high levels of the NOTCH receptors, while the corresponding ligands were widely expressed in endothelial cells, suggesting a strong interaction between pre-OBs and ECs during the osteoblastogenic process [71]. ...
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... analyses showed apparently increased interactions of receptor-ligand pairs associated with Ephrin-Eph signaling between ECs and Pre-OB, such as EFNA1-EPHA7, EPHA2-EFNA5, EPHA4-EFNB3, EPHA4-EFNA5, and EPHB4-EFNB3 ( Figure 7D-E, Figure S12, and Table S9). We next examined the anatomic relationship between Ephrin A1-expressing ECs (CD31 + ) and Eph A7-expressing Pre-OBs (ALP + ) in periodontal tissues from HC and PD samples, using quadruple immunofluorescence (IF) staining on paraffin section. ...
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... observed numerous Eph A7 + ALP + Pre-OBs on alveolar bone surfaces in samples from HC group. In contrast, Eph A7 + ALP + Pre-OBs numbers in PD samples were markedly reduced, and numerous Ephrin A1-expressing ECs were detected ( Figure 7F). ...
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... potential cross-talks with the focus on the osteoimmunology microenvironment of periodontal tissue after initial periodontal therapy could be abstracted from our data (Figure 7, Figure S10-13, and Table S9) as exemplified in Figure 8. These scRNA-seq data were direct evidence for a shared regulatory network among osteoimmune cells in periodontal tissue after initial periodontal therapy. ...
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... membranebound molecules mediate contact-dependent and bidirectional signaling through both the Eph receptors (termed forward signaling) and ephrin ligands (referred to as reverse signaling) [88]. In our study, the pronounced changes in the expression of Ephrin-Eph interactions indicated that they may play distinct roles in modulating the process of periodontitis (Figure 7, Figure S13, and Table S9). Evidence suggests that ephrin ligands and Eph receptors are crucial signaling molecules, contributing to fibroblast activation, extracellular matrix deposition, and tissue fibrosis formation [89][90][91][92]. ...
Context 17
... current study reveals the function of venous ECs in the recruitment of T cells via the production of proinflammatory cytokines and chemokines ( Figure 5 and Figure S6). New research has revealed that ECs have many innate immune functions, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular pattern-and danger-associated molecular pattern sensing, proinflammatory, immuneenhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity, suggesting ECs are novel immune cells [107][108][109][110]. Along these lines, our data suggest ECs produce multiple proinflammatory cytokines/chemokines and possess the most interactions with other cell types ( Figure 5, Figure 7, and Table S9). In addition, the interactions related to OB differentiation were most enriched between ECs and pre-OBs ( Figure 7 and Table S9). ...
Context 18
... research has revealed that ECs have many innate immune functions, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular pattern-and danger-associated molecular pattern sensing, proinflammatory, immuneenhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity, suggesting ECs are novel immune cells [107][108][109][110]. Along these lines, our data suggest ECs produce multiple proinflammatory cytokines/chemokines and possess the most interactions with other cell types ( Figure 5, Figure 7, and Table S9). In addition, the interactions related to OB differentiation were most enriched between ECs and pre-OBs ( Figure 7 and Table S9). Thus, we agree with the concept that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. ...
Citations
... In addition to pericytes (ACTA2, TAGLN, RGS5) and endothelial cells (CD31, EMCN, COL4A1), ligament cells can be divided into 6 groups of cells, including 2 groups of ligament cells (C5: chond1 and C2: chond2) with high expression of cartilagerelated markers (COL2A1, ACAN, C2orf40) 36 and 2 groups of ligament cells (C3: fibo1 and C1: fibo2) with high expression of fibroblast-related markers (COL3A1, COL6A1, IGFBP6). 37 There is also a cluster of ossified ligament cells (C8: osteo) with high expression of osteogenesis-related genes (BGLAP, RUNX2, SP7) 36 and PRG4 + progenitor cells (C6: progenitor, Fig. 3b, Fig. S5c). PRG4 + cells are considered stem cells in heterotopic ossification. ...
Ossification of the Posterior Longitudinal Ligament (OPLL) is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone, resulting in limited spinal mobility and nerve compression. Employing both bulk and single-cell RNA sequencing, we elucidate the molecular characteristics, cellular components, and their evolution during the OPLL process at a single-cell resolution, and validate these findings in clinical samples. This study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in vivo. Notably, our study identifies LOXL2 as a key regulator in this process. Through gain-and loss-of-function studies, we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament cells. It acts via the HIF1A pathway, promoting the secretion of downstream VEGFA and PDGF-BB. This function is not related to the enzymatic activity of LOXL2. Furthermore, we identify sorafenib, a broad-spectrum tyrosine kinase inhibitor, as an effective suppressor of LOXL2-mediated vascular morphogenesis. By disrupting the coupling between vascularization and osteogenesis, sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone mass. These findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.
... Certain products of the immune response, such as matrix metalloproteinases 23 have been implicated in this phenomenon, and it was recently shown that Foxp3 + T-cell-derived Th17 (exFoxp3 + Th17) cells are involved in the pathogenesis of experimental periodontitis 24,25 . Furthermore, single-cell RNA sequencing (scRNA-seq) studies have characterized immune cells that are active during the pathogenesis, furthering our understanding of the mechanisms underlying periodontitis [26][27][28] . However, these studies are usually performed exclusively on gingival samples, although periodontal tissue is composed of the gingiva, periodontal ligament, alveolar bone, and cementum 29 . ...
Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2⁻ fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss in the acute phase of periodontitis, along with macrophage polarization towards a classically activated phenotype and increased neutrophil infiltration, indicating a protective role of the IL-33/ST2 axis in acute inflammation. Thus, our findings highlight the hidden role of the peri-root tissue and simultaneously advance our understanding of the etiology of periodontitis via implicating the IL-33/ST2 axis.
... In the context of oral mucosa, broblasts had been recognized for their roles in regulating immune microenvironment [18,19] . However, the diversity and speci c functions of these heterogeneous cell populations in OLP remain elusive. ...
Stromal-immune cells interaction and their contribution in the pathogenesis of oral mucositis, remained not fully understood. This made it hard to clarify the underlying mechanism linking systemic immunity and regional immune microenvironment. The present study aims to elucidate the underpinnings of oral lichen planus (OLP) by focusing on the role of inducible tertiary lymphoid structures (iTLSs) and their impact on disease progression. Employing single-cell RNA sequencing and multiple immunofluorescences, we identified distinct cellular compositions and stromal-immune cells interactions within the iTLSs of OLP. We particularly highlighted the role of CCL19 ⁺ fibroblasts and HEV cells. These stromal cells might play a crucial role in facilitating lymphocytes trafficking from peripheral blood to the local inflammation sites within oral mucosa, thereby promoting the formation of iTLSs in OLP. Our findings also revealed a significant correlation between the presence of iTLSs and increased severity of OLP, marked by more atrophic-erosive forms and higher REU scores in patients with iTLSs. The present research offered new insights into the pathogenic mechanisms of OLP, proposing the stromal-immune cell interactions within iTLSs as essential factors in the disease's inflammatory milieu. These findings contributed to uncovering the specific regional pathological features in OLP. Hence, the characterization of iTLSs provided a fundamental foundation for further studies in oral mucosal immunity.
... As innate immune cells, macrophages act as the main initiators of immune response 7 and play critical roles in periodontitis. 8,9 Their functions on inflammation and alveolar bone resorption have been given widely attentions. 10,11 From very early on, researchers focused on the two extreme phenotypes of macrophages: proinflammatory macrophage M1 (surface marker: CD86) versus the anti-inflammatory macrophage M2 (surface marker: CD206). ...
Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss. With the progression of periodontitis, the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption. CD301b ⁺ macrophages are specific to the osteoimmunology microenvironment, and are emerging as vital booster for conducting bone regeneration. However, the key upstream targets of CD301b ⁺ macrophages and their potential mechanism in periodontitis remain elusive. In this study, we concentrated on the role of Tim4, a latent upstream regulator of CD301b ⁺ macrophages. We first demonstrated that the transcription level of Timd4 (gene name of Tim4) in CD301b ⁺ macrophages was significantly upregulated compared to CD301b ⁻ macrophages via high-throughput RNA sequencing. Moreover, several Tim4-related functions such as apoptotic cell clearance, phagocytosis and engulfment were positively regulated by CD301b ⁺ macrophages. The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages. The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b ⁺ macrophages as periodontitis progressed. Furthermore, the deficiency of Tim4 in mice decreased CD301b ⁺ macrophages and eventually magnified alveolar bone resorption in periodontitis. Additionally, Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b ⁺ macrophages phenotype. In a word, Tim4 might regulate CD301b ⁺ macrophages through p38 MAPK signaling pathway in periodontitis, which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.
... Fig. 4 Relationships between macrophage clusters in arthritis, periodontitis and osteoclastic precursors. Different macrophagic clusters found in rheumatoid arthritis (Alivernini et al. 163 ), periodontitis (Chen et al. 164 ) in humans and in arthritic mice (Culemann et al. 165 ) by single cell transcriptomics and the possible link between these clusters and osteoclastic precursors described in humans or mice upon homeostatic or inflammatory conditions Inflammatory osteoclast precursors in RA and periodontitis E Hascoët et al. ...
Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from “classical osteoclasts” has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.
... [2][3][4] Notably however, clinical patient-based single-cell sequencing studies of periodontal tissue indicate that there are associated problems such as depletion of osteoblast lineages and insufficient bone regenerative vitality after periodontal treatment. 5 There is therefore an urgent need to identify a "booster" in periodontal tissues that can directly and potently regulate the osteogenic lineage, and facilitate the development of new immunomodulatory therapeutic strategies. ...
... 24 Notably however, a recent study indicated that after conventional periodontal therapy there are problems of osteogenic lineage depletion and insufficient osteogenic activity that echo the irreversible bone loss associated with clinical periodontitis. 5,25 Therefore, how to activate the vitality of the osteoblast lineage and restore periodontal bone height is a critical challenge to be overcome. ...
Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b ⁺ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b ⁺ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b ⁺ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b ⁺ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b ⁺ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the “core” and mouse neutrophil membrane as the “shell” was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b ⁺ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b ⁺ macrophages, and suggests a CD301b ⁺ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.
... 73 Differential expression analysis between TNL and TIL groups was performed for each cluster using MAST through the "FindMarkers" function in Seurat, with a minimum pct of 0.5. 74,75 Pathway enrichment analyses were performed using DAVID (version 6.8) and Gene Set Enrichment Analysis with the Reactome, WikiPathways, and KEGG databases. 76 ...
Background:
The transition of the myometrium from a quiescent to a contractile state during labour is known to involve inflammation, which is characterized by the infiltration of immune cells and the secretion of cytokines. However, the specific cellular mechanisms underlying inflammation in the myometrium during human parturition are not yet fully understood.
Methods:
Through the analysis of transcriptomics, proteomics, and cytokine arrays, the inflammation in the human myometrium during labour was revealed. By performing single-cell RNA sequencing (scRNA-seq) and spatiotemporal transcriptomic (ST) analyses on human myometrium in term in labour (TIL) and term in non-labour (TNL), we established a comprehensive landscape of immune cells, their transcriptional characteristics, distribution, function and intercellular communications during labour. Histological staining, flow cytometry, and western blotting were applied to validate some results from scRNA-seq and ST.
Results:
Our analysis identified immune cell types, including monocytes, neutrophils, T cells, natural killer (NK) cells and B cells, present in the myometrium. TIL myometrium had a higher proportion of monocytes and neutrophils than TNL myometrium. Furthermore, the scRNA-seq analysis showed an increase in M1 macrophages in TIL myometrium. CXCL8 expression was mainly observed in neutrophils and increased in TIL myometrium. CCL3 and CCL4 were principally expressed in M2 macrophages and neutrophils-6, and decreased during labour; XCL1 and XCL2 were specifically expressed in NK cells, and decreased during labour. Analysis of cytokine receptor expression revealed an increase in IL1R2, which primarily expressed in neutrophils. Finally, we visualized the spatial proximity of representative cytokines, contraction-associated genes, and corresponding receptors in ST to demonstrate their location within the myometrium.
Conclusions:
Our analysis comprehensively revealed changes in immune cells, cytokines, and cytokine receptors during labour. It provided a valuable resource to detect and characterize inflammatory changes, yielding insights into the immune mechanisms underlying labour.
... Certain products of the immune response such as matrix metalloproteinases 23 have been implicated in this phenomenon, but it was recently shown that Foxp3 + T cell-derived Th17 cells (exFoxp3 Th17 cells) are involved in the pathogenesis of experimental periodontitis 24,25 . Furthermore, studies using single-cell RNA sequencing (scRNA-Seq) have characterized the immune cells that are active during the pathogenesis and thus advanced our understanding of the mechanisms underlying periodontitis [26][27][28] . However, these studies have usually been performed exclusively on gingival samples, even though the periodontal tissue is in fact composed of the gingiva, periodontal ligament, alveolar bone, and cementum 29 . ...
Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. However, studies on immune responses are usually based on gingival tissue, although periodontal tissue is actually comprised of four different components. Here, we have developed a novel model to analyze the pathogenesis of periodontitis with different periodontal tissue components. We have found that the inflammatory response in the peri-root tissues and the expression of interleukin (IL)-6 and nuclear factor κ-Β ligand (RANKL) by Thy-1.2 – fibroblasts/stromal cells were prominent during the course of bone destruction. Furthermore, a comprehensive analysis of the initiation phase confirmed these findings while revealing a high level of expression of ST2 (also known as IL33R and encoded by Il1rl1 ) in the peri-root tissue. Il1rl1 and Il33 deficient mice exhibited exacerbated bone loss in the acute phase of periodontitis, demonstrating the protective role of the IL-33/ST2 axis in acute inflammation. Thus, the findings obtained with this novel model show the crucial role of the peri-root tissue and advance our understanding of the etiology of periodontitis.
... In addition, TNFRSF21 is reported to be involved in the transcription of inflammatory cytokines and fibrogenesis. 33,34 On the contrary, it is convenient to define the expression levels of the six genes since they can be detected in plasma. ...
The study aimed to investigate the mechanism by which cancer-associated fibroblasts (CAFs) are activated by cancer cells and construct a risk model to predict the prognosis of patients with pancreatic cancer (PC) after surgery. Pancreatic stellate cells were isolated from human pancreatic tissue and co-cultured with cancer cells to verify their crosstalk. Liquid chromatography-tandem mass spectrometry was used to detect proteins secreted by cancer cells. The online tools Gene Expression Profiling Interactive Analysis, UALCAN, and the Human Protein Atlas were used to analyse gene expression in PC. Expression data from the cancer genome atlas and the clinical samples were used to develop a training receiver operating characteristic (ROC) model and an external validation ROC model, respectively. We identified that cancer cells promote the activation of inflammatory CAFs (iCAF) through secretory proteins, which promote PC metastasis. Six candidate proteins secreted by cancer cells were identified which promote iCAF formation. These proteins were highly expressed in tumours and were associated with a poor prognosis in patients with PC. Moreover, a 6-gene model was constructed to predict death risk in patients at 1, 2 and 3 years after surgery. The training areas under the ROC curves (AUC) of 1-, 2- and 3-year death risks were 0.780, 0.792 and 0. 825, respectively. The externally validated AUC of death at 3 years post-surgery was 0.728. In conclusion, cancer cell-secreted proteins play a vital role in iCAF formation, and the 6-gene model may be a potential marker for predicting whether PC patients will benefit from surgery.
... To our knowledge, this was the first study to identify ERS-related biomarkers of periodontitis based on microarray datasets. Single-cell sequencing and RNA-seq data that do not rely on predesigned probes are now increasingly used because of their high sensitivity and ability to detect novel genes [33,34]. However, the samples of periodontitis using these two methods are now too few in the public platform to be analyzed on a large scale. ...
Objective:
To screen for potential endoplasmic reticulum stress- (ERS-) related biomarkers of periodontitis using machine learning methods and explore their relationship with immune cells.
Methods:
Three datasets of periodontitis (GSE10334, GES16134, and GES23586) were obtained from the Gene Expression Omnibus (GEO), and the samples were randomly assigned to the training set or the validation set. ERS-related differentially expressed genes (DEGs) between periodontitis and healthy periodontal tissues were screened and analyzed for GO, KEGG, and DO enrichment. Key DEGs were screened by two machine learning algorithms, LASSO regression and support vector machine-recursive feature elimination (SVM-RFE); then, the potential biomarkers were identified through validation. The infiltration of immune cells of periodontitis was calculated using the CIBERSORT algorithm, and the correlation between immune cells and potential biomarkers was specifically analyzed through the Spearman method.
Results:
We obtained 36 ERS-related DEGs of periodontitis from the training set, from which 11 key DEGs were screened by further machine learning. SERPINA1, ERLEC1, and VWF showed high diagnostic values (AUC > 0.85), so they were considered as potential biomarkers for periodontitis. According to the results of the immune cell infiltration analysis, these three potential biomarkers showed marked correlations with plasma cells, neutrophils, resting dendritic cells, resting mast cells, and follicular helper T cells.
Conclusions:
Three ERS-related genes, SERPINA1, ERLEC1, and VWF, showed valuable biomarker potential for periodontitis, which provide a target base for future studies on early diagnosis and treatment of periodontitis.
